Technology

In the Front Lines Against AIDS

July 29, 2002

When Dani Bolognesi came to New York from Forgaria, Italy (north of Venice), in 1958 to study science, virology hadn't yet become an established field in medicine. Though vaccines existed for polio and smallpox, for the most part, viruses still weren't well understood. Bolognesi's first project at Rensselaer Polytechnic Institute in Troy, N.Y., where he began his research career, was to study characteristics of the Newcastle virus, which kills chickens and is similar in many ways to human viruses.

"I started at Rensselaer as a physicist, but that was not to my liking, so I moved on to biophysics and soon after, the structure of viruses," recalls Bolognesi, 61, who most recently co-founded AIDS research company Trimeris (TRMS) in Durham, N.C. "I became fascinated with viruses."

That began to pay off in the early 1980s, when the AIDS epidemic burst on the scene. Antiviral drug research began to focus on humans, and Bolognesi moved to Duke University to study the disease. He's still there, helping lead research into new drugs that attack strains of the AIDS virus -- HIV -- that have become resistant to what until now have been effective treatments.

"A MAJOR STEP." The first antiviral drug was AZT, or Retrovir, an AIDS drug created by scientists at Borroughs-Wellcome labs in Research Triangle, N.C. -- in conjunction with Duke researchers including Bolognesi. AZT, which is now used in a drug cocktail for AIDS, is a "nucleoside reverse transcriptase inhibitor" -- sometimes called a "nuke." It interferes with -- or blocks -- an enzyme that allows HIV to replicate.

"Looking back," Bolognesi says, "AZT wasn't very effective. But it was a major step forward. It showed us that we could make a drug that, for a short time at least, could stop a virus." Perhaps more important, "I think it catalyzed drug development in viral research because, until that time, there wasn't much confidence in the idea that you could stop viruses the way you can stop bacteria with antibiotics," he says.

AZT proved to be a forerunner to a half-dozen or more other drugs that are now used in the three- to four-drug cocktails that many HIV patients are given today. While the "nukes" account for one-half of the AIDS cocktails, the other half are protease inhibitors, which attack a protein that plays a crucial role in the spread of mature viral particles to healthy cells. Developed in the mid-1990s, protease inhibitors proved so effective initially in suppressing the virus that after many years of rising AIDS mortality in the U.S., the number of deaths began to decline substantially by 1997.

INTOLERABLE EFFECTS. Now, however, the virus appears to be winning again. In the past year or two, the number of AIDS deaths in the U.S. has stopped declining, according to preliminary data from the Centers for Disease Control in Atlanta. In the 1990s, it turns out, many people who took the AIDS cocktails didn't follow their regimen properly. Some patients had to swallow nearly 40 pills a day, an ordeal in itself.

Worse, the drugs often caused debilitating intestinal and neurological side effects that made them all but intolerable, Bolognesi says. "For other people, the drugs simply weren't enough to surmount a significant challenge to the infection," he adds.

Beyond those shortfalls, the disease went unchecked in other parts of the world. While nearly 1 million people in North America are living with HIV or AIDS, more than 40 million are afflicted worldwide, with 5 million new infections in 2001 alone, according to a recent U.N. report. Whatever the reasons -- including erratic or inconsistent treatment -- some strains of the virus have grown resistant to the cocktails that seemed so promising and that, until recently, lowered the death toll from AIDS.

DOCKING DISRUPTERS. Now researchers at companies such as Trimeris are trying to unravel the mystery of the drug-resistant strains of HIV. They've found that the virus is changing its shape, mixing up its DNA, and mutating into a predator unrecognized by many of the 17 anti-HIV drugs now on the market. With those drugs now less effective, finding new ones to fight AIDS has become crucial. And Bolognesi and his company have come up with a potentially effective new weapon.

Bolognesi, along with a group of Trimeris researchers led by his partner, Tom Matthews, have created a compound called T-20 that may become the first in a new class of HIV medicines. The drugs are called fusion inhibitors, which means they disrupt the "docking" of the virus to a healthy cell membrane so the viral matter has no effect on the cell.

To understand how the drug works, first consider that HIV, like other viruses, lacks the ability to reproduce on its own. It must first invade a T cell -- a critical component of the body's immune system -- and use the cell's own machinery to make copies of itself. This replication typically results in the formation of hundreds of viral particles and the death of the vital T cell. The virus takes hold as that process is repeated millions of times over.

PREVENTING ENTRY. Bolognesi and Matthews realized that some viruses, including HIV, must undergo a complex process called fusion in order to enter the host cell and reproduce. During fusion, the outer membrane of the virus merges with the surface of the T cell. If HIV can't fuse or dock itself to the cell, then it can't reproduce and subsequently kill the T cell.

Better yet, by blocking HIV before it gains entry to a cell, fusion inhibitors are less likely to interact adversely with other drugs or interfere with natural biochemical processes. This could be a major advantage, because it may decrease the likelihood of side effects, Bolognesi says.

Trimeris' T-20 is in final-stage testing, and the clinical evidence seemingly shows that it's effective against drug-resistant strains of the virus. If approved by the Food & Drug Administration within the next year as expected, T-20 will be delivered by injection. This makes it more difficult to take than the pills many patients on the current cocktail therapy are accustomed to. But it nonetheless offers hope to the thousands of HIV-positive people who have suffered a relapse because their drug cocktails no longer work. "The drug continues to outdo our expectations," says Bolognesi. "The data is very strong, the safety profile looks very good."

DON'T RUSH IT. While he sounds confident, Bolognesi adds that his company has learned a few lessons from watching more aggressive biotech companies such as ImClone Systems (IMCL) move too fast on their clinical trials -- only to find that an FDA panel of medical experts is unsatisfied with the evidence that a drug works well and is safe.

Says Bolognesi: "I recall as we were trying to explain to the many interested parties how we were designing our trials and how much time and money we should spend on them, a lot of people outside the company were in a hurry. They were saying that the drug looks like a no-brainer, seems very safe, so why would we need all this clinical data. Why not do less? We resisted those urgings and did not rush on this drug."

It's important to realize, moreover, that T-20 can be only a temporary solution even if it works against the newest strains of HIV. The virus is bound to scramble its DNA once again, perhaps growing resistant to T-20 and other fusion inhibitors still in development.

DIRECT ASSAULTS. Meantime, competing companies such as Merck (MRK) and Vaxgen (VXGN) are working on vaccines to counter the mutations of the virus -- a more elegant mode of fighting the disease because it inolves training the body to develop its own antibodies rather than using lab-produced drugs. "While these new drugs are important, the way to really control the disease is with a vaccine," Bolognesi says.

In addition to his work at Trimeris, he has helped establish a lab at the Duke University Center for AIDS Research that participates in all the HIV vaccine clinical trials sponsored by the National Institutes of Health. Bolognesi says he has tremendous respect for immunologists such as Merck's Emilio Emini who are tackling HIV more directly than ever before.

An HIV vaccine almost certainly remains years away. Yet for a generation or two of HIV sufferers, Dani Bolognesi and his drug T-20 could be ray of hope until a way is found to at long last eradicate AIDS. By David Shook in New York